The implantation or insertion of a medical device into a patient's body can cause the body to exhibit adverse physiological reactions. The reactions may range from infections to the formation of emboli or clots in blood vessels. One particularly adverse physiological reaction is the result of epithelial damage to the cardiovasculature. That is, the vasculature can be damaged during procedures such as percutaneous transluminal coronary angioplasty (PCTA). As a result of damage to the epithelium of the vasculature, a cascade of physiological events may result in the re-narrowing (restenosis) of the vessel. While not completely understood, restenosis may be the result of smooth muscle cell proliferation in the intimal layers of the vessel.
Restenosis of an artherosclerotic coronary artery after PTCA occurs in 10-50% of patients undergoing this procedure and subsequently requires either further angioplasty or coronary artery bypass graft. In order to maintain the patency of the vessel, intravascular stents have been developed as a mechanical means of preventing the collapse or abrupt closure of the dilated segment of the artery.
Compared to PTCA, coronary stenting has a reduced restenosis rate. The angiographic restenosis rate for coronary stenting is about 10 to 20% in short lesions and large vessels. In-stent restenosis, however, occurs in over 30% to 60% of patients with diabetes, diffuse lesions, or lesions that occur in small vessels or are located at a bifurcation (Mehran R, et al. Circulation 1999; 100:1872-8). It is known that stenting prevents restenosis by eliminating negative remodeling and elastic recoil. However, stents fail to prevent neointimal proliferative response due to vessel injury. Studies have shown that stent-induced neointimal formation is more extensive and protracted than that provoked by PTCA (Schwartz R S. J Invas Cardiol 1996; 8:386-7; Rogers C, et al. Circulation 1993; 88:1215-21). In particular, intimal hyperplasia is the major component of late lumen loss after stent implantation.
Despite a high rate of procedural success with stent implantation, an unacceptably high (approximately 25%) rate of stent thrombosis is also experienced (Serruys P W et al. N Engl J Med 1991; 324: 13-7; Schatz R A et al. Circulation 1991; 83:148-61). With the use of aggressive and precise anti-platelet and anti-coagulation therapy along with the implementation of high pressure balloon expansion, recent studies have shown thrombosis rates of less than 2% when stents are implanted electively and thrombosis rates of less than 5% in the treatment of abrupt closure (Lablanche J M, et al. Eur Heart J 1996; 17:1373-80; Goods C M, et al. Circulation 1996; 93:1803-8). Although thrombosis rates are lower as compared to the results from the early studies, stent thrombosis is a disastrous complication that carries a high risk of ischemic sequelae. For example, data from several trials show rates of myocardial infarction and death of 61% and 12%, respectively (Mak K H et al. J Am Coll Cardiol 1996; 2 7:494-503). Additionally, systemic anti-platelet and anti-coagulation therapy increases the incidence of bleeding complications. Accordingly, there still remains a need for solution to stent thrombosis.
One approach to improve the biocompatibility of stents is to incorporate bioactive or pharmacological agents onto the stents. Various techniques have been utilized to immobilize bioactive agents onto relatively inert surfaces of stents. One such technique involves coupling bioactive agents onto stent surfaces via covalent bonding. For example, U.S. Pat. No. 4,613,665 issued to Larm describes the coupling of heparin with reactive aldehyde groups to an aminated surface. Also, U.S. Pat. Nos. 5,112,457 and 5,455,040 issued to Marchant disclose the use of a similar approach to end-bind heparin on modified substrates. The substrate modification consists of depositing a film of plasma polymerized N-vinyl-2-pyrrolidone and attaching a spacer (such as PEG) on the film. The end group of the spacer is a primary amine, which can be bonded to aldehyde-ended heparin through reductive amination.
While useful, the covalent bonding approach has various shortcomings. For instance, this approach generally involves a series of chemical reactions performed directly on the surfaces of the device which only allows a single layer of bioactive agents to be attached to the surfaces. As a result, limited amounts of bioactive agents may be applied to the surface of the stent. Moreover, if excessive reagents or reactants are used in the covalent bonding process, stent functionality can be compromised by minimizing the stent's ability to be fully expanded. Also, release of such active agents from the stent surface may not be possible or very limited because the active agents are chemically bonded to the stent surface.
An alternative method to covalent bonding approach involves physically blending or dispersing bioactive agent(s) with inert polymers. These “inert” polymers do not possess any known pharmacological activity and only serve as a carrier or binder for the bioactive agent(s). For instance, bioactive compounds such as heparin have been applied to stent surfaces utilizing inert polymers such as thermoplastic polyurethane, silicone, polycaprolactone, polylactic acid, polyethylene-vinyl acetate and cellulose-based polymers.
The use of inert polymers in drug coatings permits larger doses of drugs to be applied to the medical device surface and concomitantly larger amounts of the drugs may be released. However, there remains the difficulty of combining multiple drugs having different physical properties. For example, a hydrophobic drug and a hydrophilic drug could not be concomitantly applied because they are not miscible. In order to incorporate such a drug combination, multiple chemical reaction steps, or multiple physical deposition steps including micronizing the drug for dispersion are necessary. These multiple reaction/deposition steps generally are cumbersome and costly. Furthermore, the uniformity of the drug coating and drug release rates are often difficult to control. Thus, there still remains a need for uniform drug coatings that are capable of controllably delivering multiple drugs to a site of injury.